Paullones are potent inhibitors of glycogen synthase kinase-3β and cyclin-dependent kinase 5/p25
Paullones are potent inhibitors of glycogen synthase kinase-3β and cyclin-dependent kinase 5/p25
复制标题
DOI：
10.1046/j.1432-1327.2000.01673.x
复制
发表时间：
2000-10-01
期刊：
影响因子：
--
通讯作者：
Meijer, L
中科院分区：
文献类型：
--
作者：
Leost, M;Schultz, C;Meijer, L
保乐酮类化合物是一类具有良好抗肿瘤活性的苯并氮卓酮类化合物。它们最近被描述为细胞周期调节细胞周期依赖的蛋白依赖性激酶(CDKs)的有效的、ATP竞争性的抑制物。我们在此报道，泡桐内酯也是糖原合成酶-3β(GSK-3β)(IC50：4-80 nM)和神经元CDK5/p25(IC50：20-200 nM)的非常有效的抑制剂。这两种酶是微管结合蛋白tau过度磷酸化的主要原因，这是在阿尔茨海默病和其他神经退行性疾病患者的大脑中观察到的一个特征。Alsterpaullone是最活跃的paullone，通过与ATP竞争与GSK-3β结合而发挥作用。在阿尔茨海默病中，Alsterpaullone在体内抑制tau的磷酸化，这些位点通常被GSK-3β磷酸化。Alsterpaullone在体外也抑制依赖CDK5/p25的小鼠纹状体脑片中DARPP-32的磷酸化。白藜芦酮的这种双重特性可能会使这些化合物成为研究以及可能治疗神经退行性和增殖性疾病的非常有用的工具。
Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3 beta (GSK-3 beta) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3 beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3 beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.